Mammalian SIRT1 represses forkhead transcription factors
Mammalian SIRT1 represses forkhead transcription factors
The NAD-dependent deacetylase SIR2 and the forkhead transcription factor DAF-16 regulate lifespan in model organisms, such as yeast and C. elegans. Here we show that the mammalian SIR2 ortholog SIRT1 deacetylates and represses the activity of the forkhead transcription factor Foxo3a and other mammalian forkhead factors. This regulation appears to be in the opposite direction from the genetic interaction of SIR2 with forkhead in C. elegans. By restraining mammalian forkhead proteins, SIRT1 also reduces forkhead-dependent apoptosis. The inhibition of forkhead activity by SIRT1 parallels the effect of this deacetylase on the tumor suppressor p53. We speculate how down-regulating these two classes of damage-responsive mammalian factors may favor long lifespan under certain environmental conditions, such as calorie restriction.
Acetylation Acetyltransferases/*metabolism Animals Apoptosis Blotting, Northern Blotting, Western Cell Cycle Proteins/*metabolism Cell Line DNA-Binding Proteins/*metabolism Dose-Response Relationship, Drug Down-Regulation Embryo, Mammalian/cytology Forkhead Box Protein O1 Forkhead Transcription Factors Gene Expression Regulation Genes, Reporter HeLa Cells Histone Acetyltransferases Histone Deacetylases/metabolism/*physiology Humans Mice Mice, Knockout PTEN Phosphohydrolase Phosphoric Monoester Hydrolases/metabolism Plasmids/metabolism Precipitin Tests Protein Binding Sirtuin 1 Sirtuins/metabolism/*physiology Stem Cells/metabolism Transcription Factors/*metabolism Transcription, Genetic Tumor Suppressor Protein p53/metabolism Tumor Suppressor Proteins/metabolism Up-Regulation p300-CBP Transcription Factors
551-563
Motta, M. C.
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Divecha, N.
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Lemieux, M.
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Kamel, C.
fc93beb7-0f15-4983-bb49-819124abd0b8
Chen, D.
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Gu, W.
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Bultsma, Y.
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McBurney, M.
81922aff-2882-4328-8fea-079805b1f298
Guarente, L.
4a8bcf97-663a-4bef-9a10-4afea2da8fd9
20 February 2004
Motta, M. C.
4822866a-d6fa-43aa-ad23-8f1e2c3f5b8e
Divecha, N.
5c2ad0f8-4ce7-405f-8a15-2fc4ab96d787
Lemieux, M.
94769e0b-6e50-4a7d-a657-ccb27ee7ccd5
Kamel, C.
fc93beb7-0f15-4983-bb49-819124abd0b8
Chen, D.
b6e622c7-82f3-4707-99b9-9bc608e73676
Gu, W.
0c1f7c32-d483-48eb-84ce-57aaa43b3817
Bultsma, Y.
7c07501a-75ac-4731-b38e-fefea9bd6884
McBurney, M.
81922aff-2882-4328-8fea-079805b1f298
Guarente, L.
4a8bcf97-663a-4bef-9a10-4afea2da8fd9
Motta, M. C., Divecha, N., Lemieux, M., Kamel, C., Chen, D., Gu, W., Bultsma, Y., McBurney, M. and Guarente, L.
(2004)
Mammalian SIRT1 represses forkhead transcription factors.
Cell, 116 (4), .
(doi:10.1016/s0092-8674(04)00126-6).
Abstract
The NAD-dependent deacetylase SIR2 and the forkhead transcription factor DAF-16 regulate lifespan in model organisms, such as yeast and C. elegans. Here we show that the mammalian SIR2 ortholog SIRT1 deacetylates and represses the activity of the forkhead transcription factor Foxo3a and other mammalian forkhead factors. This regulation appears to be in the opposite direction from the genetic interaction of SIR2 with forkhead in C. elegans. By restraining mammalian forkhead proteins, SIRT1 also reduces forkhead-dependent apoptosis. The inhibition of forkhead activity by SIRT1 parallels the effect of this deacetylase on the tumor suppressor p53. We speculate how down-regulating these two classes of damage-responsive mammalian factors may favor long lifespan under certain environmental conditions, such as calorie restriction.
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Published date: 20 February 2004
Additional Information:
Motta, Maria Carla Divecha, Nullin Lemieux, Madeleine Kamel, Christopher Chen, Delin Gu, Wei Bultsma, Yvette McBurney, Michael Guarente, Leonard eng Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. 2004/02/26 Cell. 2004 Feb 20;116(4):551-63. doi: 10.1016/s0092-8674(04)00126-6.
Keywords:
Acetylation Acetyltransferases/*metabolism Animals Apoptosis Blotting, Northern Blotting, Western Cell Cycle Proteins/*metabolism Cell Line DNA-Binding Proteins/*metabolism Dose-Response Relationship, Drug Down-Regulation Embryo, Mammalian/cytology Forkhead Box Protein O1 Forkhead Transcription Factors Gene Expression Regulation Genes, Reporter HeLa Cells Histone Acetyltransferases Histone Deacetylases/metabolism/*physiology Humans Mice Mice, Knockout PTEN Phosphohydrolase Phosphoric Monoester Hydrolases/metabolism Plasmids/metabolism Precipitin Tests Protein Binding Sirtuin 1 Sirtuins/metabolism/*physiology Stem Cells/metabolism Transcription Factors/*metabolism Transcription, Genetic Tumor Suppressor Protein p53/metabolism Tumor Suppressor Proteins/metabolism Up-Regulation p300-CBP Transcription Factors
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Local EPrints ID: 479778
URI: http://eprints.soton.ac.uk/id/eprint/479778
ISSN: 0092-8674
PURE UUID: ae58e5a0-c7c1-4f35-aab1-81e149d2c08f
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Date deposited: 26 Jul 2023 17:01
Last modified: 17 Mar 2024 03:00
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Author:
M. C. Motta
Author:
M. Lemieux
Author:
C. Kamel
Author:
D. Chen
Author:
W. Gu
Author:
Y. Bultsma
Author:
M. McBurney
Author:
L. Guarente
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